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Presentation
The network and its partners
History of transplantation  |
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Mechanisms of allograft tolerance
IMMUNE ALLOGRAFT TOLERANCE
The usual therapy for patients transplanted with an organ or tissue of someone else, is based on immunossuppressive drug treatment. These drugs prevent the graft from acute rejection but are of low efficiency to prevent chronic rejection which occur several years after transplantation. Moreover, these drugs can have side effects, such as an increase of risks of cardiovascular disease outcomes, diabetes, cancers and infectious diseases. The induction of tolerance regarding the graft, is defined as the lack of immune response harmfull against the donor's antigens expressed by the transplanted organ - which are differents from those of the donor - while preserving the recipient's capacity to repond to foreign antigens, especially microbial pathogens. Such a successful tolerant state would be the real solution regarding problems linked to organ transplantation. First, tolerance induction would allow, even entirely suppress, the systematic use of immunossupressor drugs. Secondly, by allowing longterm graft survival, tolerance induction would avoid to make a second, or event a third transplant, as it frequently the case, in case of a loss of the first graft. This would obviously represents a potential solution regarding the overall lack of organs. Finaly, tolerance induction would also make possible to bring an end to issues of risk/benefit ratios for transplantation of non life-saving organs such as composite tissue, pancreas or pancreatic islets in diabetic patients without renal failure. Research based on strategies allowing immune tolerance induction, as well as means to detect and study it, is a major challenge which is currently and only supported by the academic sector. Although much effort is still required for tolerance induction, some promising success have been recently obtained in clinical research.
RESEARCH DEVELOPPED BY CENTAURE AIMING AT A SPECIFIC IMMUNE ALLOGRAFT TOLERANCE
Teams of the CENTAURE network have various but relevant approaches for sucessful allograft tolerance induction. CENTAURE can significantly contributes to this field though international collaboration, by emphasizing basic research based on cellular and in vitro molecular immune tolerance work, using a wide array of animal models (approximatively 100 original articles on the subject), by its capacity for experimental transfer to pre-clinical models (primate transplantation facility, unique in France and in Europe) and humans (clinical use of new products derived from biotechnology such as monoclonal antibodies, combination of molecules for example)
MAIN RESEARCH AIMS
- Study of stem cells. Some stem cells (mainly mesenchymal stem cells), in addition to their inner properties of regeneration of multiple tissues, have immunomodulative effects coming from mechanisms not yet well understood. This study aims at elucidating these mechanisms.
- Cellular therapy using specific immune cells. Dendritic cells are amongst cells that can be used in cellular therapy protocols aiming at the induction of tolerance. Dendritic cells are at the heart of immune responses and they allow, under some experimental conditions, to induce immune tolerance. Regulatory T cells are other potentially interesting cells. This aim optimises conditions of use in these various cell types in therapeutic protocols on rodents and on primates, with a potential clinical application.
- Precise dissection of immune mechanisms which underlies tolerance. A thorough analysis of immune cells and genes that are expressed in animal models of tolerance and in tolerant patients, is aimed at identifying "biomarkers" related to tolerance and allowing its detection in a reliable manner. This would lead us - on the long view - to propose a gradual and controlled weaning or event withdrawal in immunosuppressive treatement, for patients in which an immune tolerant state regarding graft is identified.
- Analysis of new genes identified in tolerance models. Genes with unknown functions have been identified, thanks to systematic and comparative studies for gene expression, in tolerant or in organ rejection situations, in animal models as well as in transplanted patients. Expressed functions from molecules which are coded by these genes are analysed in vitro on human and rodent cells and analysed in vivo in these rodent models. These studies will allow the identification, among these molecules, the ones that can be developped as drugs inducing tolerance.
- Study of therapeutic tools derived from biotehcnology and facilitating immune tolerance induction. Monoclonal antibodies or protein combination allowing a "reset function" of lymphocytes involved in rejection can extend in a larger part, even in a final way, the survival of transplanted tissues and organs. Though some of these tools, especially anti- CD3 antibodies, are already used in humans in a clinical dimension which is not connected to transplantation, their use for kidney graft is quite innovative. This research aim goes along with studies aiming at a better interaction understanding, in these rodent models of these drugs.
